A Look Forward: New and Emerging Therapies

Brad S. Kahl, MDSkoronski Chair of Lymphoma Research

University of Wisconsin School of Medicine and Public HealthAssociate Director for Clinical Research

UW Carbone Cancer Center

Changing Landscape

• FDA approvals last 12 months– Obinutuzumab for CLL– Lenalidomide for MCL– Ibrutinib for MCL and CLL

• Horizon– Idelalisib for indolent NHL– ABT-199 for CLL, NHL– CART therapy

Examples of How We Treat

• Hodgkin lymphoma– ABVD + IFRT

• Diffuse Large B-cell Lymphoma– R-CHOP + IFRT

• Follicular Lymphoma– R-bendamustine or R-CHOP + maintenance rituximab

• CLL/SLL– FCR or R-bendamustine

“Everything works better with R”

• Rituximab added to CHOP increased cure rate in DLBCL by 15% (absolute difference)

• Rituximab added to chemotherapy increased 5-yr PFS by 20% and OS by 5% in FL.

• Major effort into development of new moAbs.– Target different Ags– New “improved” anti-CD20s

Proposed Mechanisms of Action of RituximabProposed Mechanisms of Action of Rituximab

Anderson et al. Biochem Soc Trans. 1997;25:705; Golay et al. Blood. 2000;95:3900; Reff et al. Blood. 1994;83:435; Clynes et al. Nat Med. 2000;6:443; Shan et al. Cancer Immunol Immunother. 2000;48:673; Silverman et al. Arthritis Rheum. 2003;48:1484.

Macrophage,Macrophage,monocyte, ormonocyte, ornatural killer cellnatural killer cell

CDCCDCCDCCDC

FcFcRI, FcRI, FcRII, FcRII, FcRIIIRIII

Cell lysisCell lysis

CD2CD200

CD2CD200

Cell lysisCell lysis

MACMAC

Complement activation Complement activation (C1qC1rC1s)(C1qC1rC1s)

ApoptosisApoptosisApoptosisApoptosis

B B cellcell

RituximabRituximab ADCCADCC

MoAb’s for Lymphoma

FDA approved

• Rituximab (CD20)• Alemtuzumab (CD52)• Ofatumomab (CD20)• Obinutuzimab (CD20)• Zevalin (CD20) -Y90

• Bexxar (CD20) -I131

• Brentuximab vedotin (CD30) -MMAE

Dropped• Lumiliximab (CD23)• Galiximab (CD80)• Epratuzumab (CD22)• Hu1D10 (HLA DR)• SGN-30 (CD30)• SGN-40 (CD40)

Under Study• Biosimilars (CD20)

Type I (rituximab) vs Type II (obinutuzimab)Type I (rituximab) vs Type II (obinutuzimab)

ANTIBODY TYPE I II

LIPID RAFTS YES NO

CDC HIGH LOW

ADCC + +

DIRECT CYTOTOXICITY WEAK STRONG

BINDING SITES 2 1

HOMOTYPIC AGGREGATION

WEAK STRONG

TYPE I TYPE IIFREE END

Adapted from Cragg MS Blood 2011

CLL11: Phase III Study of Chlorambucil (Chl) Alone vs Chl + Obinutuzumab vs Chl + Rituximab in Previously

Untreated CLL Patients With Comorbidities

GA101 + chlorambucil × 6 cycles

Rituximab + chlorambucil × 6 cycles

Primary endpoint: PFS (investigator assessed)

Secondary endpoints:ORRDORDFSOSMRD

R

Chlorambucil = 0.5 mg/kg d1, d15 q28d (based on GermanCLLSG CLL5 study)

GA101=100 mg d1, 900 mg d2, 1000 mg d8, 15 cycle 1; 1000 mg d1 cycles 2-6

Rituximab=375 mg/m2 d1 cycle 1; 500 mg/m2 d1 cycles 2-6 q28d (GCLLSG CLL8)

1:2:2

DATA (from PI)Stage I analysis, ASCO 2013 and FDA data, of G-Chl vs Chl

Stage 2 analysis of G-Chl vs R-Chl, ASH PLENARY

Progression-FreeSurvival

11mos 23mos

Obinutuzumab

• FDA approval Nov 1st

– For use in combination with chlorambucil– First line CLL treatment

• Unknown if “FCO” or “BO” will be superior to FCR or BR

CLL: CART Therapy

T Cell

CLL CART

CD19

Targeted agents

• Principle– Find the driver of growth for a particular

cancer (in the lab)– Identify this driver in your patients (predictive

biomarker)– Attack the pathway with the correct kinase

inhibitor or other small molecule “disruptor”

I wish it were this simple

Figure 1A: B cell receptor pathway. Taken from http://www.cellsignal.com/reference/pathway/B_Cell_Antigen.html

Challenges

• Reality– Numerous agents with 20-30% response

rates and median durations of 6 months

• Identifying biomarkers is hard– Assay challenges, sample challenges,

specificity challenges,

• Running biomarker driven clinical trials is difficult– Regulatory overload

Targeting Intracellular Pathways

Potential Targets

• Proteasome• RAS-RAF-MEK• Angiogenesis• Histones• mTOR• JAK-STAT• PI3 kinase• BTK• BCL-2

Agent (disease)

Bortezomib (MCL)

Sorafenib (bust)

Bevacizumab (bust)

SAHA, romidepsin (CTCL)

Temsirolimus (MCL)

SB1518 (TBD)

Idelalisib (TBD)

Ibrutinib (MCL, CLL)

ABT-199 (TBD)

Targeting the B Cell Receptor

• Pathway utilized by normal cells – Differentiation, proliferation

• Appears some B cell malignancies have “tonic” signaling through pathway– Unclear what is source of signaling

• Currently most promising area of research in B cell malignancies

LYN

CK

BTK

PLCγ

PKCβ

PI3K

SYK PP

P

B Cell ReceptorCytokine Receptor

JAK1

DAG

IP3--Ca++ MYD88

MALT1

Bcl10CARD11

AKT

NFkB

Targets of B-Cell Receptor Signaling

Transcriptional Activation

BLNK

ERK

IkBIkB

Proteosomal Degradation

Antigen

TLR

PIP3

fostamatinib

Cal 101

Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent

B-Cell Non-Hodgkin Lymphoma (iNHL)

A Gopal,1 B Kahl,2 S de Vos,3 N Wagner-Johnston,4 S Schuster,5 K Blum,6 W Jurczak,7 I Flinn,8 C Flowers,9 P Martin,10 A Viardot,11 A Goy,12 A Davies,13 PL Zinzani,14 M Dreyling,15 L Holes,16 D Li,16 R Dansey,16 Wayne Godfrey,16 and G Salles17

1University of Washington School of Medicine, Seattle, WA, USA; 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, CA, USA; 4Washington University School of Medicine, St. Louis, MO, USA; 5Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6Ohio State University Wexner Medical Center, Columbus, OH, USA; 7Jagiellonian University, Krakow, Poland; 8Sarah Cannon Research Institute, Nashville, TN, USA; 9Winship Cancer Institute of Emory University,

Atlanta, GA, USA; 10Weill Cornell Medical College, New York, NY, USA; 11University Hospital of Ulm, Ulm, Germany; 12Hackensack University Medical Center, Hackensack, NJ, USA; 13University of Southampton, Southampton, United Kingdom; 14University of Bologna, Bologna, Italy; 15University Hospital Grosshadern, LMU Munich, Germany; 16Clinical Research Oncology,

Gilead Sciences, Seattle, WA, USA; 17Hospices Civils de Lyon, University Claude Bernard, Pierre Benite, France

American Society of HematologyDecember 8, 2013 New Orleans, LA

Oral No 85.

Slide 21

Expression Ubiquitous Ubiquitous Leukocytes Leukocytes

EC50 (nM) >10,000 1419 2500 9

Selective, oral inhibitor of PI3K-delta Inhibits proliferation and induces apoptosis in many

B-cell malignancies Inhibits homing and retention of malignant B-cells

in lymphoid tissues reducing B-cell survival

Idelalisib

Class I PI3K Isoform

♦ Promising activity in R/R iNHL in phase I study*

*Benson D et al. ASCO 2013, abstr 8526

Slide 22

aCriterion for lymphadenopathy response [Cheson 2007]b 3 subjects no post baseline evaluation: □ 2 subjects NE ■ 1 subject PD by Lymph Node biopsy

Study 101-09 Waterfall Plot Lymph Node Response

-100

-75

-25

0

-50a

+25

+50

Individual Patients (N=125)

SP

D o

f M

easu

red

Lym

ph

No

des

,B

est

% C

han

ge

fro

m B

asel

ine

•90% had improvement in lymphadenopathy•57% had ≥50% decrease from baseline

Slide 23

Study 101-09: Duration Of Response (DOR)

Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments

Median DOR = 12.5 months

0

25

50

75

100

0 (71)

3(54)

6(34)

9(17)

12(9)

15(0)

18(0)

Time from Response, Months(N, Patients at Risk)

% C

on

tin

ued

Res

po

nse

Slide 24

AE Any Grade

N, %Grade ≥ 3

N, % Diarrhea 54 (43%) 16 (13%) Fatigue 37 (30%) 2 (2%) Nausea 37 (30%) 2 (2%) Cough 36 (29%) None Pyrexia 35 (28%) 2 (2%) Dyspnea 22 (18%) 4 (3%) Decreased appetite 22 (18%) 1 (1%) Abdominal pain 20 (16%) 3 (2%) Vomiting 19 (15%) 3 (2%) URI 18 (14%) None Decreased weight 17 (13%) None Rash 16 (13%) 2 (2%) Asthenia 14 (11%) 3 (2%) Night Sweats 14 (11%) None Pneumonia 14 (11%) 9 (7%)

Study 101-09: Adverse Events > 10%

Idelalisib

• I think there is a good chance idelalisib will get FDA approval in this patient population

LYN

CK

BTK

PLCγ

PKCβ

PI3K

SYK PP

P

B Cell ReceptorCytokine Receptor

JAK1

DAG

IP3--Ca++ MYD88

MALT1

Bcl10CARD11

AKT

NFkB

Targets of B-Cell Receptor Signaling

Transcriptional Activation

BLNK

ERK

IkBIkB

Proteosomal Degradation

Antigen

TLR

PIP3

fostamatinib

Cal 101

ibrutinib

PCI-32765: First-in Class Inhibitor of BTK

• Forms a specific and irreversible bond with cysteine-481 in BTK

• Highly potent BTK inhibition at IC50 = 0.5 nM

• Orally administered with once daily dosing resulting in 24-hr target inhibition

• In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation

• Inhibits CLL cell migration and adhesion

• No cytotoxic effect on T-cells or NK-cells

27

Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010Herman SEM et al: Blood 117: 6287-6296, 2011Ponader, et al., ASH Meeting Abstracts 116:45, 2010

N

N

N

N

NH 2

O

N

O

PCI-32765

Original Article Targeting BTK with Ibrutinib in Relapsed or

Refractory Mantle-Cell Lymphoma

Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D., Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D., Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D.,

Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D., Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D.,

Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang,

Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A.

Blum, M.D.

N Engl J MedVolume 369(6):507-516

August 8, 2013

Best Response to Therapy.

Wang ML et al. N Engl J Med 2013;369:507-516

Duration of Response, Progression-free Survival, and Overall Survival.

Wang ML et al. N Engl J Med 2013;369:507-516

Backround

• Limited options for R/R CLL• Bruton’s tyrosine kinase

– Essential component of B cell receptor signaling

• Ibrutinib (PCI-32765)– 1st in class oral BTK inhibitor

• Phase 1b-2 multicenter trial – 420 mg/day N = 51– 840 mg/day N = 34

Figure 1: lymphocyte count vs. nodal response

Figure 1: Response over time

Figure 3: PFS and OS

Conclusions

• Unprecedented single agent activity in relapsed MCL and CLL

• Durable responses• Side effect profile tolerable

– Lack of myelosuppression– Infection risk similar to background

• FDA approval – Nov 2013 MCL– Feb 2014 CLL

Ongoing Research

• BCR pathway inhibitors are:– Most active: CLL/SLL, MCL– Moderate: FL, MZL, MALT, DLBCL

• Extensive ongoing research– In other lymphoma types– In combination with chemotherapy and other

targeted agents

BCL-2 targeting

39

Introduction

• Bcl-2 overexpression is fundamental in the pathophysiology of

NHL(Sawas et al, Curr Opin Hematol, 2011)

• BH3 mimetic Navitoclax (ABT-263) is active in indolent NHL and

CLL (Wilson et al, Lancet Oncology, 2010 and Roberts et al, J Clin Oncol, 2012)

– Inhibits Bcl-2, Bcl-xL and Bcl-w

– Thrombocytopenia due to Bcl-xL inhibition is dose-limiting

• ABT-199: a small molecule, orally-bioavailable second-

generation BH3-mimetic (Souers et al., Nature Medicine in press)

• >100-fold selectivity for Bcl-2 over Bcl-xL in tumor cell line assays

O NH

O

O2S

HN

N

N

Cl

NO2

O

N NH

ABT-199

Adverse Events (AEs)

All Grades ≥20% of pts

n (%)Diarrhea 29 (43)

Nausea 27 (40)

Neutropenia 25 (37)

Fatigue 22 (33)

Upper respiratory tract infection 22 (33)

Cough 15 (22)

Grades 3/4 ≥ 3 pts

n (%)Neutropenia 24 (36)

Anemia 6 (9)

Thrombocytopenia 6 (9)

Tumor lysis syndrome* 6 (9)

Febrile neutropenia 5 (7)Hyperglycemia 5 (7)Hypophosphatemia 3 (4)*TLS includes 3 events from Cohort 1; 2 clinical events and 1 laboratory TLS occurred in Cohorts 4, 8, and 2

40

% C

ha

ng

e F

rom

Ba

se

line

-100

-80

-60

-40

-20

0

20

400 mg (3)

600 mg (4)

600 mg (5)

300 mg (2)

200 mg (1)

MCLMCL MCLMCL MCLMCL DLBCLDLBCL MCLMCL WMWM MCLMCL MCLMCL WMWM

FLFLFLFL

DLBCLDLBCLFLFL FLFLFLFLMCLMCL FLFL FLFL DLBCLDLBCL FLFLWMWM

****

**

**

* = Confirmed Partial Remission**CR = Complete Remission* = Confirmed Partial Remission**CR = Complete Remission

CRCR

Median Time to 50% Reduction = 43 days (range 36 to 113; n=11)

NHL Maximal % Reduction in Nodal Size

n = 21 evaluable (at minimum 6 week assessment)**Confirmed = response verified at 2nd consecutive assessment n = 21 evaluable (at minimum 6 week assessment)**Confirmed = response verified at 2nd consecutive assessment

Dose (cohort)Dose (cohort)

Best Percent Change from Baseline in SPD of Nodal Massby CT Scan• 50/57 (88%) patients had at least a 50% reduction in sum of the product of diameters (SPD) of nodal masses.• The median time to 50% reduction was Week 6.

42

SPD = Sum of the product of diameters; SE = safety expansion.N = 57 evaluable (at minimum, Week 6 assessment)

del (17p)

Fludarabine refractory

del(17p) and FR

FR

17p

»

Conclusions for ABT-199

• ABT-199 highly active, acceptable safety profile

• Once daily oral dosing

• Tumor lysis syndrome is a risk

• Response rate in CLL/SLL is 79% (84 patients)– Phase II dose 400 mg/day

• Response rate in NHL is 48% (44 patients)– Phase II dose 1200 mg/day

• ABT-199 is highly promising as a single agent and in should be studied in combination

Efficacy in CLL/SLL• 45 year old male with CLL/SLL, diagnosed in 2007

• Prior therapies:

– FCR x 6 cycles (PR for 9 months)– Bendamustine-Rituximab x 6 cycles (PR for 12 months)– R-CHOP x 3 cycles (minor response. Stopped for toxicity) – BR for 3 cycles (minor response)– High dose steroids (minor response)

• November 2nd 2013, began ABT-199

March 27 2012

Week 6

May 9 2012

Week 16

February 8 2012

Baseline

January 14 2013Oct 25, 2013 Dec 10, 2013 Feb 17, 2014

Conclusions

• Not truly ready to discard chemotherapy…• However,

– Targeted agents are finally showing highly promising results in B cell malignancies

– BCR inhibitors, BCL-2 inhibitors

• Challenge is to develop rational combinations of targeted agents– Disrupt several key survival pathways simultaneously– Delay/prevent emergence of resistance

• I am optimistic

Questions?